title: MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging.
abstract: In a previous study, we reported that a deficiency in MnSOD activity (approximately 80% reduction) targeted to type IIB skeletal muscle fibers was sufficient to elevate oxidative stress and to reduce muscle function in young adult mice (TnIFastCreSod2(fl/fl) mice). In this study, we used TnIFastCreSod2(fl/fl) mice to examine the effect of elevated oxidative stress on mitochondrial function and to test the hypothesis that elevated oxidative stress and decreased mitochondrial function over the lifespan of the TnIFastCreSod2(fl/fl) mice would be sufficient to accelerate muscle atrophy associated with aging. We found that mitochondrial function is reduced in both young and old TnIFastCreSod2(fl/fl) mice, when compared with control mice. Complex II activity is reduced by 47% in young and by approximately 90% in old TnIFastCreSod2(fl/fl) mice, and was found to be associated with reduced levels of the catalytic subunits for complex II, SDHA and SDHB. Complex II-linked mitochondrial respiration is reduced by approximately 70% in young TnIFastCreSod2(fl/fl) mice. Complex II-linked mitochondrial Adenosine-Tri-Phosphate (ATP) production is reduced by 39% in young and was found to be almost completely absent in old TnIFastCreSod2(fl/fl) mice. Furthermore, in old TnIFastCreSod2(fl/fl) mice, aconitase activity is almost completely abolished; mitochondrial superoxide release remains > 2-fold elevated; and oxidative damage (measured as F(2) - isoprostanes) is increased by 30% relative to age-matched controls. These data show that despite elevated skeletal muscle-specific mitochondrial oxidative stress, oxidative damage, and complex II-linked mitochondrial dysfunction, age-related muscle atrophy was not accelerated in old TnIFastCreSod2(fl/fl) mice, suggesting mitochondrial oxidative stress may not be causal for age-related muscle atrophy.
authors.affiliation: Department of Physiology, University of Texas Health Science Center at San Antonio, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lustgarten
authors.forename: Youngmok C
authors.initials: YC
authors.lastname: Jang
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Wenbo
authors.initials: W
authors.lastname: Qi
authors.forename: Yuejuan
authors.initials: Y
authors.lastname: Qin
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Dahia
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.forename: Arunabh
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Florian L
authors.initials: FL
authors.lastname: Muller
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.forename: Holly
authors.initials: H
authors.lastname: Van Remmen
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000375:Aging; D000818:Animals; D028441:F2-Isoprostanes / Q000032:analysis; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D013481:Superoxides / Q000032:analysis
chemical_list: D028441:F2-Isoprostanes; D007527:Isoenzymes; D013481:Superoxides; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D013385:Succinate Dehydrogenase; D000154:Aconitate Hydratase